Lactamimides as calcium antagonists

ABSTRACT

Applicants have discovered that certain previously known lactamimide derivatives possess, as a class, valuable calcium channel blocking activity. By virtue of this calcium antagonism activity the compounds are antihypertensives and will have other activities associated with calcium antagonists.

This invention relates to the use of certain lactamimides as calciumantagonists and their pharmaceutical uses as antiangina, vasodilating,antihypertensive, antimanic, and anticonvulsant agents and forprotection against ischemic injury and for conditions where an excess ofintracellular calcium is known to be detrimental to the organism.

BACKGROUND OF THE INVENTION

The compounds described herein are known. The compounds employed in thismethod have been described in the following patents: U.S. Pat. No.3,894,002, issued July 8, 1975; U.S. Pat. No. 3,852,269, issued Dec. 3,1974; Belgian Pat. No. 783,276 granted Apr. 30, 1973; U.S. Pat. No.3,873,520 issued Mar. 25, 1975; U.S. Pat. No. 3,803,170 issued Apr. 9,1974; U.S. Pat. No. 3,838,151 issued Sept. 24, 1974; U.S. Pat. No.3,833,559 issued Sept. 3, 1974; U.S. Pat. No. 3,783,162 issued Jan. 1,1974; U.S. Pat. No. 3,900,565 issued Sept. 19, 1975; U.S. Pat. No.3,881,006 issued Apr. 29, 1975; Belgian Pat. No. 814,114 granted May 15,1974; U.S. Pat. No. 3,840,524 issued Oct. 8, 1974; U.S. Pat. No.3,816,457 issued June 11, 1974; U.S. Pat. No. 3,890,445 issued June 17,1975; U.S. Pat. No. 3,845,071 issued Oct. 29, 1974; U.S. Pat. No.3,840,523 issued Oct. 8, 1974; Great Britain Pat. No. 1,201,848 issuedNov. 4, 1970; U.S. Pat. No. 3,378,438 issued Apr. 16, 1968.

It has been shown that calcium antagonists of diverse chemical structureinteract in an allosteric manner with the calcium ion-channel protein.The chemical classes are exemplified by verapamil (a phenylalkylaminederivative), diltiazem (a benzothiazepine derivative) and thedihydropyridines, for example, nitrendipine. In binding experimentsusing [3H]nitrendipine as the ligand, it has been shown that diltiazemenhances binding whereas verapamil displaces [3H]nitrendipine in anon-competitive manner.

The compound N-(cis-2-phenylcyclopentyl)azacyclo-tridecan-2-imine.HCl, alactamimide has been reported to inhibit stimulated adenylate cyclaseactivity in a number of tissues. In addition, the compound has negativeinotropic and chronotropic effects on isolated guinea pig hearts andthese effects are reversed by the administration of calcium. Recently itwas reported that this compound enhanced [3H]nitrendipine binding in ratcerebral cortical and cardiac homogenates in a similar manner todiltiazem and selectively reduced calcium currents with a potencysimilar to diltiazem.

We have now discovered that analogs of the above lactamimides belong toa novel chemical class displaying diltiazem-like calcium antagonism andare useful in the treatment of a wide variety of medical conditions.

SUMMARY OF THE INVENTION

Calcium channel blocking can be accomplished by the administration of acompound of the following general formula, or a pharmaceuticallyacceptable salt thereof or the individual geometric or optical isomerswhere applicable: ##STR1## wherein Z is hydrogen or lower alkyl of from1 to 4 carbon atoms;

n is an integer of from 3 to 16;

R is

(A) a straight or branched alkyl group of from 8 to 15 carbon atoms; ora lower alkoxyalkyl group wherein the alkyl moiety has from 8 to 15carbon atoms and the alkoxy moiety has from 1 to 4 carbon atoms;

(B) the group phenylalkyl wherein the alkyl moiety has from 1 to 6carbon atoms and wherein the phenyl moiety is unsubstituted orsubstituted in which case the substituents may be attached at the ortho,meta or para-position of the phenyl ring and are chlorine, fluorine,bromine, lower alkyl having from 1 to 4 carbon atoms, lower alkoxyhaving from 1 to 4 carbon atoms, hydroxy or methylenedioxy;

(C) the group ##STR2##

wherein A' is a straight or branched alkylene group of from 1 to 6carbon atoms or benzyl and is attached to either the 1- or 2-position ofthe naphthalene ring, which is either unsubstituted or is mono- ordi-substituted with a chlorine, fluorine, bromine, trifluoromethyl, astraight or branched alkyl group of from 1 to 12 carbon atoms, an alkoxygroup of from 1 to 3 carbon atoms or NO₂ ;

(D) the group 1- or 2-adamantyl or 1- or 2-norbornyl;

(E) the group ortho, meta or para-binphenylyl;

(F) the group 9-fluorenyl which is unsubstituted or substituted in whichcase the substituents may be attached to any one of the four availablecarbon atoms of each aromatic ring and are chlorine, bromine, fluorine,a lower alkyl group having from 1 to 4 carbon atoms, a lower alkoxygroup having from 1 to 4 carbon atoms or NO₂ ;

(G) dibenzocycloheptenyl;

(H) the group ##STR3##

wherein X is oxygen or sulfur, A is a bond or an alkylene chain of from1 to 3 carbon atoms, and R¹ hydrogen, a straight or branched lower alkylgroup having from 1 to 4 carbon atoms, a straight or branched loweralkenyl group having from 3 to 6 carbon atoms, cycloalkyl of from 3 to 6carbon atoms or phenyl;

(I) the group ##STR4##

wherein R² is phenyl or a cycloalkyl group having from 3 to 6 carbonatoms, and R³ is hydrogen or methyl;

(J) the group ##STR5##

wherein W is a straight or branched alkylene chain having from 2 to 6carbon atoms which is substituted with one phenyl group on any of the 6carbon atoms with the proviso that the carbon atom adjacent to theexocyclic nitrogen atom must have at least one hydrogen attached to it;

(K) the group ##STR6##

wherein R⁵ is oxygen, sulfur, --CH₂ --, --CH₂ CH₂ -- or --CH═CH--, andR⁶ is hydrogen or a lower alkyl group of from 1 to 4 carbon atoms;

(L) the group ##STR7## wherein R⁷ is cycloalkyl of from 3 to 5 carbonatoms, R⁸ is hydrogen, lower alkoxy of from 1 to 4 carbon atoms or loweralkyl of from 1 to 4 carbon atoms, and p is the integer 1 or 2;

(M) the group ##STR8##

wherein R⁹ is hydrogen, a straight or branched lower alkyl group of from1 to 4 carbon atoms, chlorine, fluorine, bromine, CF₃, SCF₃, OCF₃,phenyl, phenoxy or a lower alkoxy group of from 1 to 4 carbon atoms andq is an integer of from 1 to 3;

(N) the group ##STR9##

wherein R¹⁰ is a lower alkyl group of from 1 to 4 carbon atoms, R¹¹ ishydrogen or lower alkyl of from 1 to 4 carbon atoms, R¹² is an alkylgroup having from 8 to 14 carbon atoms, an alkoxy group having from 8 to14 carbon atoms, a cycloalkyl group having from 5 to 14 carbon atoms,phenyl, phenoxy, phenylalkyl wherein the alkyl moiety has from 1 to 4carbon atoms, phenylalkoxy wherein the alkoxy moiety has from 2 to 4carbon atoms, 2,2-diphenylvinyl or fluoren-9-ylidene;

(O) the group ##STR10##

wherein the phenyl moiety is attached to the ##STR11##

moiety through the 1- or 2-position of the phenyl ring, R¹³ is a loweralkyl group of from 1 to 4 carbon atoms and R¹⁴ and R¹⁵ taken togetherare (--CH₂ --)₃, --CH₂ CH₂ C(CH₃)₂ --, --(CH₂)₄ -- or --C(CH₃)₂ CH₂ CH₂C(CH₃)₂ --; with the proviso that when R is the group ##STR12## Z ishydrogen; and pharmaceutically acceptable acid addition salts thereof.

DETAILED DESCRIPTION OF INVENTION

It is apparent from the foregoing general Formula I that all of thecompounds utilized in the instantly claimed invention contain alactamimide ring having the structure ##STR13## wherein n is an integerof from 3 to 16. Thus, the heterocyclic ring of the lactamimide moietycan be, for example, pyrrolidine, piperidine, hexahydroazepine,octahydroazocine, octahydroazonine, azacyclodecane, azacycloundecane,azacyclododecane or azacyclotridecane each of which is attached to theexocyclic nitrogen of the lactamimide moiety through the 2-position.

The term "dibenzocycloheptenyl" as used herein means both5H-dibenzo[a,d]cycloheptenyl and 5H-dibenzo[a,c]cycloheptenyl whereinthe open valency is on any of the saturated carbon atoms of thecycloheptane ring. That is, the term dibenzocycloheptenyl means

5H-dibenzo[a,d]cyclohepten-5-yl,

5H-dibenzo[a,d]cyclohepten-10(or 11)-yl,

5H-dibenzo[a,c]cyclohepten-5(or 7)-yl, and

5H-dibenzo[a,c]cyclohepten-6-yl.

It is readily apparent that many of the "R" groups of the compounds offormula 1 have geometric or optical isomers. Unless specificallyindicated, the individual isomers and their mixtures are intended.

For convenience and uniformity the compounds described herein arerepresented and named as substituted 2-iminoperhydroazacarbocyclics, asrepresented by general Formula I. It is known that compounds of thistype as acid addition salts may also be represented by the tautomericform illustrated by the following general Formula II: ##STR14## Thistautomerism has been discussed by R. Kwok and P. Pranc, J. Org. Chem.32, 740 (1967). Structures of this formula could be named differently.In solution under the conditions of the therapeutic utility theproportions of each tautomeric form or the delocalization of the chargebetween the two nitrogen atoms will be dependent upon numerous factorsincluding the nature of the substituents and the pH of the medium. Thisequilibrium state is conveniently illustrated by the following generalFormula III: ##STR15## The compounds of general Formula I wherein R isother than the group ##STR16## as acid addition salts can exist ineither tautomeric form, and it is understood that this invention relatesto the use of compounds represented or named in either tautomeric form.In the above general Formulas II and III, the various symbols R, Z and nhave the meanings defined in general Formula I. Further, when Z has themeaning hydrogen, other generally known tautomerism can occur.

Compounds of general Formula I wherein R represents ##STR17## and Zrepresents hydrogen may exist as a cyclic tautomer of the followinggeneral Formula IV. ##STR18## In the above general Formula IV thevarious symbols n, R₂, and R₃ have the meanings defined in generalFormula I. It is understood that this invention embraces the use of thecompounds of general Formula I wherein R is the group ##STR19## when inthe form as represented by general Formula IV. For purposes ofconvenience the compounds of this type are named herein as the cyclicform.

The compounds of the invention possess pharmacological activity andtherefore they can be used as medicines. With the term "use" allindustrial applicable aspect and acts of said use, including theirembodiment into pharmaceutical compositions are intended. In particular,the compounds of the invention show in vitro calcium-antagonist activityand in vivo antihypertensive action. The compounds are thus useful asantianginals, vasodilators, antihypertensives, antimanics,anticonvulsants, and antiischemics and for those conditions in which anexcess of intracellular calcium ion is involved, the so-called Ca²⁺overload hypothesis.

The ability of the compounds listed in Table 1 to act as calciumantagonists has been demonstrated in the following tests.

[³ H]d-cis-Diltiazem binding assays

The whole brain from male Sprague-Dawley rats (200-300 g) was dissectedand homogenized in cold 50 mM Tris-HCl buffer (pH 7.4) for 2×30 secondperiods by Polytron (Brinkmann, setting No. 5). The homogenate waswashed 2 times (48,000×g for 10 minutes, 4° C.) with intermittentresuspension of the pellet in fresh buffer. The final pellet wasresuspended to an original tissue concentration of 100 mg/ml in Tris-HClbuffer. The binding assay of [³ H]d-cis-diltiazem was performed aspreviously described by J. L. Balwierczak and A. Schwartz, Eur. J.Pharmacol. 116:193-194, (1985) and H. Schoemaker and S. Z. Langer, Eur.J. Pharmacol. 111:273-277, (1985). Briefly, a 100 μl aliquot of thehomogenate was incubated with 2.5 nM [³ H]d-cis-diltiazem in a totalvolume of 1 ml in 50 mM Tris-HCl buffer (pH 7.4) for 60 minutes at 25°C. or at 37° C. The reaction was terminated by rapid filtration under avacuum through 0.05% polyethylenimine-pretreated Whatman GF/B glassfiber filters. Filters were immediately washed 2 times with 4 ml of coldTris-HCl buffer. Pretreatment of the filters with 0.05% polyethylenimineserved to eliminate [³ H]d-cis-diltiazem binding to the filter. Thefilters were dried and the radioactivity in the filters was extractedovernight in scintillation fluid. Samples were counted by liquidscintillation spectrophotometry with an efficiency of 43%. Specific [³H]d-cis-diltiazem binding was defined as the difference in bindingdetermined in the absence and presence of 30 μM d-cis-diltiazem and itrepresented 50-55% of the total amount of filter-retained radioactivity.Compounds were examined at concentrations from 10⁻⁸ to 10⁻³ M for theirability to inhibit [³ H]-diltiazem binding to membranes. pKi values weredetermined by the method of Cheng and Presoff, Biochem Pharmacol. 22:3099-3108 (1973).

[³ H]Nitrendipine binding assay

Membranes were prepared from the hearts of male Sprague-Dawley rats and[³ H]nitrendipine binding was conducted as described in detail by H. R.Lee, et al., J. Pharmacol Exo. Ther. 233:611-616, (1985), as modified byF. J. Ehlert, et al., Biochem. Biophys. Rec. Common. 104:937-943,(1982). The ability of compounds tested at 10⁻⁶ and 10⁻⁷ M to enhance [³H]nitredepine binding was taken as indicative of diltiazem-like calciumantagonistic properties.

K.sup.± -depolarized taenia and small intestine

Strips of taenia from the caecum or pieces of ileum, 2 cm in length,from male guinea pigs (200-400 g) were set up in isolated organ baths inCa⁺⁺ -free K⁺ Tyrode's solution (mM NaCl 137, KCl 40, NaH₂ PO₄ 0.4,NaHCO₃ 11.9, glucose 5.5) and gassed with 95% O₂, 5% CO₂ at 37° C.Contractions were measured with isotonic transducers with a 1 g load.Cumulative dose-response curves were obtained. Tissues were then washedand incubated with the test compounds for 20-25 minutes and then Ca⁺⁺concentration response curves re-established. The preparations wereshown to be stable for at least 5 hours and to give reproducibledose-response curves to Ca⁺⁺. Dose ratios were determined graphically atED₅₀ values from the Ca⁺⁺ dose-response curve and Schild plots wereconstructed to determine pA₂ value using inverse regression lineanalysis. Alternatively, when only one concentration of an antagonistwas used, pA₂ values were calculated according to the method of J. M.Van Rossum, Arch. Int. Pharmacodyn Ther. 143: 299-330 (1963).

The results of these tests are summarized in Tables 2 and 3 and in FIGS.1-4.

                                      TABLE 1                                     __________________________________________________________________________    Calcium Antagonist and [.sup.3 H]Diltiazem                                    Displacing Properties of Lactamimides                                         Test Compound                                                                 Number                                                                        (as HCl unless other-                                                         wise indicated)                                                                          n  R                  pA.sub.2 *                                                                       pKi**                                     __________________________________________________________________________     1         11                                                                                ##STR20##         7.27                                                                             6.49                                       2         11                                                                                ##STR21##         6.59                                                                             6.51                                       3         11                                                                                ##STR22##         6.66                                                                             6.41                                       4         11                                                                                ##STR23##         6.07                                                                             5.92                                      5V         6                                                                                 ##STR24##         6.60                                                                             N.T.                                       6         5                                                                                 ##STR25##         6.64                                                                             N.T.                                       7         4                                                                                 ##STR26##         6.15                                                                             N.T.                                       8         6                                                                                 ##STR27##         6.63                                                                             6.72                                       9         5                                                                                 ##STR28##         5.86                                                                             6.17                                      10         5                                                                                 ##STR29##         6.33                                                                             6.08                                      11         5                                                                                 ##STR30##         5.60                                                                             5.92                                      12         5                                                                                 ##STR31##         5.54                                                                             5.54                                      13         5                                                                                 ##STR32##         5.47                                                                             4.70                                      14         7                                                                                 ##STR33##         4.84                                                                             5.26                                      15         5                                                                                 ##STR34##         N.T.                                                                             4.16                                      16         3                                                                                 ##STR35##         N.T.                                                                             4.96                                      17 18      d-cis l-cis                                                                       ##STR36##         7.38 N.T.                                                                        7.42 5.39                                 19         3                                                                                 ##STR37##         N.T.                                                                             N.T.                                      20         5  CH.sub.2 CH.sub.2 CH(C.sub.6 H.sub.5).sub.2                                                      6.19                                                                             N.T.                                      21         5                                                                                 ##STR38##         6.14                                                                             --                                        22         5                                                                                 ##STR39##         6.31                                                                             --                                        23         4                                                                                 ##STR40##         6.04                                                                             --                                        24         6                                                                                 ##STR41##         6.63                                                                             --                                        25         5                                                                                 ##STR42##         5.47                                                                             --                                        26         5                                                                                 ##STR43##         5.18                                                                             --                                        __________________________________________________________________________     V = Fumarate                                                                  N.T. -- Not Tested                                                            *pA2 values calculated by the method of O. Arunlakshana & H. O. Schild,       Br. J. Pharmacol. Chemother. 14: 45-58 (1959) using guinea pig ileum or       taenia preparations.                                                          **pKi values calculated by the method of Y. C. Cheng & W. H. Prusoff,         Biochem. Pharmacol. 22: 3099-3108, (1973) using displacement of 3H            diltiazem to rat brain membranes at 25° C. n = 3                  

In Table 1, the chemical nomenclature for each of the test compounds isas follows:

Test Compound 1: N-(2,2-diphenylpentyl)azacyclotridecan-2-imine;

Test Compound 2: 2-(o-biphenylylimino)azacyclotridecane;

Test Compound 3: 2-[(cis-2-phenylcyclopentyl)imino]-azacyclotridecane;

Test Compound 4: 2-(2-norbornylimino)azacyclotridecane:

Test Compound 5: 2-[(2,2-diphenylpentyl)imino]octahydroazocine;

Test Compound 6: hexahydro-2-[(2,2-diphenylpentyl)imino]azepine;

Test Compound 7: 2-[(2,2-diphenylpentyl)imino]-piperidine;

Test Compound 8: 2-[[α-(1-adamantanyl)benzyl]imino]octahydroazocine;

Test Compound 9: 2-[(p-butoxy-α-phenylbenzyl)imino]hexahydroazepine;

Test Compound 10:2-[(p-chloro-α-[p-chlorophenyl]benzyl)-imino]hexahydroazepine;

Test Compound 11:hexahydro-N-[phenyl[3-(trifluoro-methyl)phenyl]methyl]-2H-azepin-2-imine;

Test Compound 12:2-[(cis-2-cyclohexylcyclopentyl)imino]-hexahydroazepine;

Test Compound 13: 2-(2-adamantanylimino)hexahydroazepine;

Test Compound 14: octahydro-2-[(cis-2-phenylcyclopentyl)-imino]azonine;

Test Compound 15: hexahydro-2-[(cis-2-phenylcyclopentyl)-imino]azepine;

Test Compound 16: 2-[(cis-2-phenylcyclopent-1-yl)imino]pyrrolidine;

Test Compound 17:(1)-cis-5-[2-(dimethylamino)ethyl]2,3-dihydro-3-hydroxy-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-oneacetate;

Test Compound 18: (1)-cis-5-[2-(dimethylamino)ethyl]2,3-dihydro-3-hydroxy-2-(p-methoxyphenyl)-1,5-benzothiazepin-4(5H)-oneacetate;

Test Compound 19: 2-methoxy-4-[[[3-[(4-methylphenyl)-methylene]-2-pyrrolidinyliden]amino]-methyl]phenol;

Test Compound 20: hexahydro-2-[3,3-diphenylpropylimino)-azepine;

Test Compound 20: hexahydro-2-(2,2-diphenylethylimino)-azepine;

Test Compound 22: hexahydro-2-[(2,2-diphenylpentyl)-imino]azepine;

Test Compound 23: 2-[(2,2-diphenylpentyl)imino]-piperidine;

Test Compound 24: 2-[(2,2-diphenylpentyl)imino]octa-hydroazocine;

Test Compound 25:(+)-hexahydro-N-[1-(1-naphthalenyl)-ethyl]2H-azepin-2-imine; and

Test compound 26:(-)-hexahydro-N-[1-(1-naphthalenyl)-ethyl]2H-azepin-2-imine.

                  TABLE 2                                                         ______________________________________                                        Temperature dependence of displacement of                                     [.sup.3 H]d-cis-diltiazem by d-cis-diltiazem and lactamides                   Compound        25° C.                                                                           37° C.                                       ______________________________________                                        d-cis-Diltiazem 43 ± 7 110 ± 25                                          3              280 ± 30                                                                             403 ± 77                                         19              1260 ± 90                                                                            1900 ± 230                                       ______________________________________                                         IC.sub.50 values were calculated from doseresponse curves at                  concentrations giving 50% inhibition of the specific [3H]dcis-diltiazem       binding to rat whole brain membranes. Ligand concentration was 2.5 nM, n      3.                                                                       

                  TABLE 3                                                         ______________________________________                                        Enhancement of [.sup.3 H]nitrendipine binding to rat heart                    membranes by d-cis-diltiazem and lactamimides                                            25° C.  37° C.                                       Compound   10.sup.-7 M                                                                            10.sup.-6 M                                                                             10.sup.-7 M                                                                           10.sup.-6 M                             ______________________________________                                        1          119 ± 6                                                                             123 ± 6                                                                               252 ± 13                                                                          224 ± 14                             2          117 ± 7                                                                              123 ± 10                                                                            152 ± 9                                                                            152 ± 15                             3          102 ± 1                                                                             112 ± 2                                                                              141 ± 8                                                                            165 ± 13                             5          --       --        111 ± 9                                                                            122 ± 3                              4          105 ± 4                                                                             106 ± 4                                                                              108 ± 7                                                                            116 ± 8                              d-cis-Diltiazem                                                                           96 ± 5                                                                              83 ± 8                                                                              218 ± 4                                                                            262 ± 10                             ______________________________________                                         Values are the mean ± SEM of single experiments run in triplicate at       the concentrations of drugs indicated. Ligand concentration was 0.1 nM an     control specific binding was 49.6 ± 1.7 fmol/mg protein.              

The compounds may be administered in various manners to achieve thedesired effect. The compounds may be administered alone or in the formof pharmaceutical preparations to the patient being treated eitherorally or parenterally, such as, intravenously or intramuscularly. Theformulation of suitable pharmaceutical compositions can be carried outby one skilled in the art according to the general common knowledge inthe art, and referring to reference books, such as Remington'sPharmaceutical Sciences Handbook, Mack Publishing Company, U.S.A. Theamount of compound administered will vary with the severity of thecondition to be treated, and the mode of administration. For oraladministration the calcium antagonist effective amount of compound isfrom about 0.01 mg/kg (milligrams per kilogram) of patients body weightper day to about 10 mg/kg of patient body weight per day and preferablyfrom about 0.05 mg/kg of patient body weight per day to about 5 mg/kg ofpatient body weight per day.

For parenteral administration the calcium antagonist effective amount ofcompound is from about 0.001 mg/kg of patient body weight per day up toabout 5 mg/kg of patient body weight per day and preferably from about0.01 mg/kg of patient body weight per day up to about 2 mg/kg of patientbody weight per day.

For oral administration a unit dosage may contain, for example, from0.50 to 100 mg of the active ingredient. For parenteral administration aunit dosage may contain, for example, from 0.05 to 70 mg of the activeingredient. Since the compounds of the invention generally possess along lasting duration of action they might be conveniently administeredonce or twice a day, however, repetitive daily administrations may be,at least in some instances, desirable and will vary with the conditionsof the patient and the mode of administration. As used herein, the term"patient" is taken to mean a warm blooded animal, humans included.

For oral administration the compounds can be formulated into solid orliquid preparations such as capsules, pills, tablets, troches, powders,solutions, suspensions or emulsions. The solid unit dosage form can be acapsule which can be of the ordinary gelatin type, either hard or soft,containing, for example, lubricants and inert fillers, such as lactose,sucrose and cornstarch. In another embodiment the compounds of theinvention can be tableted with conventional tablet bases such aslactose, sucrose and cornstarch in combination with binders, such asacacia, cornstarch or gelatin, disintegrating agents such as potatostarch or alginic acid, and a lubricant such as stearic acid ormagnesium stearate.

For parenteral administration the compounds may be administered asinjectable dosages of a solution or suspension of the compound in aphysiologically acceptable diluent with a pharmaceutical carrier whichcan be a sterile liquid such as water and oils with or without theaddition of a surfactant and other pharmaceutically acceptableadjuvants. Illustrative of oils which can be employed in thesepreparations are those of mineral petroleum, animal, vegetable orsynthetic origin. For example, peanut oil, soybean oil and mineral oil.In general, water, saline, aqueous dextrose and related sugar solutions,ethanol and glycols such as propylene glycol or polyethylene glycol canbe used as liquid carriers for injectable solutions.

For rectal administration the compounds are administered in the form ofsuppositories, admixed with conventional vehicles such as, for example,cocoa butter, wax, spermaceti, polyvinylpyrrolidone, orpolyoxyethylenglycols and their derivatives.

The compounds can be administered in the form of a depot injection orimplant preparation which may be formulated in such a manner as topermit a sustained release of the active ingredient. The activeingredient can be compressed into pellets or small cylinders andimplanted subcutaneously or intramuscularly as depot injections orimplants. Implants may employ inert materials such as biodegradablepolymers or synthetic silicones, for example, Silastic, a siliconerubber manufactured by the Dow-Corning Corporation. The oral route isgenerally the preferred route of administration of the compounds of theinvention, while the capsule is generally the preferred pharmaceuticalformulation.

An illustrative composition for tablets is the following:

    ______________________________________                                                            mg/tablet                                                 ______________________________________                                        (a)    2-(2-norbornylimino)azacyclo                                                                     15                                                         tridecane                                                              (b)    Lactose            33                                                  (c)    Corn starch        11.25                                               (d)    Sucrose 3% starch  12.75                                               (e)    Corn starch paste (10%)                                                                          1.50                                                (f)    Zinc stearate      1.50                                                ______________________________________                                    

A preferred embodiment of this invention is the use of the compoundsdescribed herein wherein n is an integer of from 0 to 16, and withinthis preferred embodiment the use of the compounds wherein n is theinteger 11 is more preferred. Also preferred are those compounds offormula 1 wherein R is selected from the groups D, E, and L. Morepreferred are those compounds of formula 1 wherein R is selected from 1-or 2-norbornyl, especially 2-norbornyl, ortho-biphenyl, or adiphenylalkyl group of from 2 to 6 carbon atoms wherein the phenylgroups are substituted on the 8 or 6 carbon atom of the alkyl chain,especially a 2,2-diphenylpentyl or 3,3-diphenylpropyl group. Especiallypreferred are those compounds of formula 1 wherein n is 11 and wherein Ris 2-norbornyul, orthobiphenyl or a 2,2-diphenylpentyl group.

Illustrative examples of compounds of this invention are

2-(8-methoxyoctylimino)azacyclotridecane,

2-(12-n-propoxydodecylimino)azacyclododecane,

hexyhydro-2-(10-butoxydecylimino)azepine,

2-(11-ethoxyundecylimino)piperidine,

2-(12-n-propoxydodecylimino)pyrrolidine,

2-(benzylimino)pyrrolidine,

2-(p-chlorobenzylimino)piperidine,

hexahydro-2-(3',4'-methylenedioxybenzylimino)azepine,

2-(p-tolylimino)azacyclodecane,

octahydro-2-(p-anisylimino)azonine,

octahydro-2-(p-n-butoxyphenethylimino)azocine,

hexahydro-2-(o-propylphenethylimino)azepine,

hexahydro-2-(o-tolylimino)azepine,

hexahydro-2-(benzylimino)azepine,

hexahydro-2-[1-(6-dodecyl-1-naphthyl)ethylimino]azepine,

2-(7-trifluoromethyl-2-naphthylmethylimino)octahydroazonine,

hexahydro-2-(1-naphthylmethylimino)azepine,

2-[1-naphthyl)ethylimino]piperidine,

2-(6-bromo-2-methoxy-1-naphthylmethylimino)azacyclotridecane,

2-[1-(5,8-dimethyl-1-naphthyl)ethylimino]hexahydroazepine,

2-[1-(1-naphthyl)ethylimino]octahydroazopine,

hexahydro-2-α-(1-naphthyl)benzylimino]azepine,

2-1(adamantylimino)azacyclotridecane,

2-(2-adamantyl)hexahydroazepine,

2-(1-adamantylimino)azacycloundecane,

1-methyl-2-(2-adamantylimino)azacyclododecane,

2-(2-adamantylimino)azacyclodecane,

2-(2-norbornylimino)azacyclododecane,

1-methyl-2-(1-norbornylimino)azacyclodecane,

2-(2-norbornylimino)piperidine,

1-ethyl-2-(2-norbornylimino)hexahydroazepine,

2-(2-norbornylimino)pyrrolidine,

2-(1-norbornylimino)azacyclotridecane,

2-(o-biphenylylimino)azacyclotridecane,

2-(m-biphenylylimino)hexahydroazepine,

1-methyl-2-(p-biphenylylimino)piperidine,

2-(o-biphenylylimino)pyrrolidine,

2-(9-fluorenylimino)azacyclotridecane,

2-(9-fluorenylimino)pyrrolidine,

2-(2-nitro-9-fluorenylimino)piperidine,

2-(3-methoxy-9-fluorenylimino)hexahydroazepine,

2-(9-fluorenylimino)octahydroazepine,

2-(3,6-dimethyl-9-fluorenylimino)hexahydroazepine,

1-methyl-2-(9-fluorenylimino)azacyclotridecane,

2-(3-methyl-7-chloro-9-fluorenylimino)azacyclododecane,

2-(9-fluorenylimino)azacycloundecane,

2-(4-bromo-9-fluorenylimino)azacyclodecane,

2-(3-n-propoxy-9-fluorenylimino)pyrrolidine,

2-(2-fluoro-9-fluorenylimino)piperidine,

2-[(10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5-yl)imino]hexahydroazepine,

2-[(10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5-yl)imino]octahydroazocine,

2-[(10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5-yl)imino]octahydroazonine,

2-[(10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5-yl)imino]azacyclotridecane,

2-[(10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5-yl)imino]azacyclododecane,

2-[(10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5-yl)imino]piperidine,

2-[(10,11-dihydro-5H-dibenzo[a,d]cycloheptan-5-yl)imino]pyrrolidine,

2-[(1-benzylcyclopentyl)imino]pyrrolidine,

2-[[α-(2-thienyl)benzyl]imino]azacyclotridecane,

2-[(2-thienyl)imino]hexahydroazepine,

1-methyl-2-(2-thienylimino)hexahydroazepine,

hexahydro-2-[1-(2-thienyl)propylimino]azepine,

2-(furfurylimino)hexahydroazepine,

2-[[α-(2-furyl)benzyl]imino]octahydroazocine,

1-ethyl-2-[[α-(2-furyl)benzyl]imino]octahydroazocine,

2-[[α-(2-thienyl)benzyl]imino]hexahydroazapine,

2-[1-(2-thienyl)propylimino]pyrrolidine,

2-[(α-cyclopropyl-2-thienyl)imino]hexahydroazepine,

2-[β-(2-thienyl)isopropylimino]hexahydroazepine,

1-[2-(1-[2-furyl]pent-4-enyl)imino]azacyclotridecane,

2-[2-(1-[2-furyl]pent-4-enyl)imino]azacyclododecane,

2-[(α-cyclopentyl-2-thienyl)imino]piperidine,

2-[(α-[2-furyl]benzyl)imino]hexahydroazapine,

2-[(3-[4-(2-furyl)-4-cyclopentyl]butylimino)azepine,

2-(-[1-(2-furyl)hex-4-enyl]imino)azacyclotridecane,

2,3,5,6,7,8-hexahydro-2-methyl-2-phenylimidazo[1,2-a]pyridin-3-ol,

2,3,6,7-tetrahydro-2-methyl-3-phenyl-5H-pyrolo[1,2-a]imidazol-3-ol,

2,3,6,7-tetrahydro-2,2-dimethyl-3-phenyl-5H-pyrrolo[1,2-a]imidazo-3-ol,

2,3,5,6,7,8,9,10-octahydro-2-methyl-3-phenylimidazo-[1,2-a]azocine-3-ol,

2,3,5,6,7,8-hexahydro-3-phenylimidazo[1,2-a]pyridin-3-ol,

3-cyclohexyl-2,3,6,7,8,9-hexahydro-2-methyl-5H-imidazo[1,2]azopine-3-ol,

hexahydro-2-[(β-methyl-β-phenylphenethyl)imino]azepine,

2-[(β-ethyl-β-phenylphenethyl)imino]octahydroazocine,

2-[(1,3-diphenylpentyl)imino]octahydroazonine,

2-[(1,3-diphenylpropyl)imino]piperidine,

2-(2,2-diphenylethylimino)hexahydroazepine,

2-(3,3-diphenylpropylimino)hexahydroazepine,

2-(2,3-diphenylpropylimino)azacyclotridecane,

2-[(α-methyl-β-phenylphenethyl)imino]hexahydroazepine,

2-(1,4-diphenylbutylimino)pyrrolidine,

1-methyl-2-(1,4-diphenylbutylimino)azacyclododecane,

2-[(β-phenyl-β-propylphenethyl)imino]azacyclotridecane,

2-[(β-isopropyl-β-phenylphenethyl)imino]hexahydroazepine,

2-(α-phenylphenethylimino)pyrrolidine,

2-[(α-methyl-β-phenethylpropyl)imino]octahydroazocine,

2-[(β-phenyl-β-propylphenethyl)imino]octahydroazonine,

1-butyl-2[1-(2-dibenzothienyl)ethylimino]pyrrolidine,

2-[1-(2-fluorenyl)ethylimino]hexahydroazepine,

2-[2-methyl-1-(3-phenanthryl)propylino]octahydroazocine,

2-[1-(2-dibenzofuranyl)propylimino]piperidine,

2-[1-(4-dibenzothienyl)ethylimino]hexahydroazapine,

2-[1-(2-fluorenyl)pentylimino]octahydroazonine,

2-[1-(9-phenanthryl)ethylimino]hexahydroazepine,

2-[1(2-phenanthryl)ethylimino]azacyclotridecane,

2-[1-(9,10-dihydro-2-phenanthryl)propylimino]azacyclodecane,

2-[1-(2-dibenzothienyl)ethylimino]-N-methylhexahydroazepine,

2-[1-(2-dibenzothienyl)ethylimino]octahydroazocine,

2-[(2-dibenzofuranyl)ethylimino]octahydroazonine,

2-[1-(3-phenanthryl)ethylimino]azacycloundecane,

2-[(α-cyclopropylbenzyl)imino]piperidine,

2-[(α-cyclopropyl-α-methoxybenzyl)imino]pyrrolidine,

2-[(α-cyclopropyl-p-butylbenzyl)imino]octahydroazopine,

2-[(α-cyclopropyl-tert-butoxybenzyl)imino]hexahydroazepine,

2-[(α-cyclobutylbenzyl)imino]azacyclotridecane,

2-(α-cyclobutyl-2,4-diethylbenzyl)imino]octahydroazocine,

2-[(α-cyclopropylbenzyl)imino]-1-methylpyrrolidine,

2-[(α-cyclopropyl-2,4-dimethylbenzyl)imino]-1-methylhexahydroazepine,

1-ethyl-2-[(α-cyclobutylbenzyl)imino]azacyclodecane,

1-propyl-2-[(α-cyclopentylbenzyl)imino]hexahydroazepine,

2-[(α-cyclobutyl-3,5-dimethoxybenzyl)imino]azacyclododecane,

2[(α-cyclopentylbenzyl)imino]octahydroazonine,

2[(α-cyclopentyl-2,4-dipropoxybenzyl)imino]azacyclotridecane,

2-[(α-cyclopentyl-p-ethoxybenzyl)imino]octahydroazocine,

2-[(bis[p-ethylphenyl]methyl)imino]octahydroazocine,

2[(p-chloro-α-phenylbenzyl)imino]hexahydroazepine,

hexahydro-2-[(α-[m-methylphenyl]-m-isopropylbenzyl)imino]octahydroazonine,

2-[(bis[p-trifluoromethylthiophenyl]methyl)imino]-piperidine,

2-[(m-[trifluoromethyl]α-phenyl]benzyl)imino]hexahydroazepine,

2-[p-chloro-α-[p-chlorophenyl]benzyl)imino]azacyclodecane,

2-[(α-[p-chlorophenyl]-m-trifluoromethylbenzyl)imino]azacycloundecane

2-[(p-tert-butyl-α-[p-chlorophenyl]benzyl)imino]-azacyclododecane,

1-methyl-2-[(α-phenyl-p-trifluoromethoxybenzyl)imino]hexahydroazepine

2-[(p-bromo-α-phenylbenzyl)imino]azacyclotridecane,

2-[(p-phenoxy-α-phenylbenzyl)imino]azacyclotridecane,

2-[(3,4,5-trimethoxy-α-phenylbenzyl)imino]azacyclododecane,

2-[(3,4-dipropoxy-α-phenylbenzyl)imino]octahydroazopine,

2-[(bis[p-trifluoromethylthiophenyl]methyl)imino]azacyclotridecane,

2-[(diphenylmethyl)imino]-1-methylpiperidine,

2-[(diphenylmethyl)imino]octahydroazocine,

2-[(diphenylmethyl)imino]-N-octahydroazonine,

2-[(m-methoxy-α-phenylbenzyl)imino]hexahydroazepine,

2-[(p-butoxy-α-phenylbenzyl)imino]octahydroazonine,

2-[(diphenylmethyl)imino]azacyclotridecane,

2-[(p-decyl-α-methylbenzyl)imino]pyrrolidine,

1-methyl-2-[α-methyl-p-3,3-diethylpentyl)benzylimino]-pyrrolidine,

1-ethyl-2-[p-(dodecyloxy)-α-methylbenzylimino]-piperidine,

2-[-methyl-p-(3,7-dimethyloctyloxy)benzylimino]-piperidine,

1-propyl-2-[α-butyl-p-cyclohexylbenzylimino]hexahydroazepine,

2-[α-methyl-p-cyclododecylbenzylimino]hexahydroazepine,

2-[2,2-diphenylvinyl)-α-isopropylbenzylimino]azacyclodecane,

2-(α-methyl-p-tridecylbenzylimino)hexahydroazepine,

2-[α,2-dimethyl-4-(3-phenoxypropoxy)benzylimino]octahydroazonine,

2-[α,5-dimethyl-2-(3-phenylethoxy)benzylimino]octahydroazocine,

2-[α,3-dimethyl-4-(3-phenylpropoxy)benzylimino]hexahydroazepine,

2-(p-dodecyloxy-2-methylbenzylimino)hexahydroazepine,

1-methyl-2-[α-methyl-p-phenoxybenzylimino]azacycloundecane,

2-[α-methyl-p-(3-phenyl-1-propen-1-yl)benzylimino]azacyclotridecane,

2-[α-methyl-p-(4-phenylbutoxy)benzylimino]azacyclododecane,

2-[p-(2-phenoxyethoxy-α-methylbenzylimino]azacyclo-tridecane,

1-[1-(1,2,3,4-tetrahydro-6-naphthyl)ethylimino]hexahydroazepine,

2-[1-(4-indanyl)ethylimino]hexahydroazepine,

2-[1-(1,2,3,4-tetrahydro-2,2,4,4-tetramethyl-6-naphthyl)propylimino]azacyclotridecane,

1-methyl-2-[1-(4-indanyl)ethylimino]azacyclododecane,

2-[1-(1,2,3,4-tetrahydro-6-naphthyl)ethylimino]piperidine,

2-[1-(1,1-dimethyl-4-indanyl)ethylimino]azacyclotridecane, and

2-[1-(4-indanyl)ethylimino]pyrrolidine.

The compounds of this invention can be prepared as described in theprior art, i.e., U.S. Pat. No. 4,061,746.

Illustrative examples of pharmaceutically acceptable salts which may beformed of the compounds employed in the present invention are those ofany suitable inorganic acids, such as hydrochloric, hydrobromic,sulfuric or phosphoric acids or any suitable organic acid, such ascarboxylic acids, such as acetic, propionic, glycolic, lactic, pyruvic,malonic, succinic, fumaric, malic, tartaric, citric, ascorbic, maleic,hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic,salicyclic, 2-phenoxybenzoic, or sulfonic acids, such as methanesulfonic or 2-hydroxyethane sulfonic acid.

EXPLANATION OF FIGURES FIG. 1 Inhibition of [³ H]d-cis-diltiazem by d-and 1-cis-diltiazem and related lactamimides

The inhibition of [³ H]d-cis-diltiazem binding was determined byincubating [³ H]d-cis-diltiazem (2.5 nM) at 25° C. with six to nineconcentrations of the drugs (Panel A ○ , d-cis-diltiazem; ○ ,1-cis-diltiazem; Panel B - ○ , Test Compound 3; ○ , Test Compound 4,Δ,Test Compound 14; □, Test Compound 16; ○ , Test Compound 15.

All solutions were freshly made before use and each point represents theaverage of three separate experiments performed in duplicate.

FIG. 2 Effect of diltiazem on Ca⁺⁺ -induced contractions of K⁺-depolarized guinea pig ileum.

Cumulative concentration response curves to Ca⁺⁺ were obtained prior to,and after, pre-incubation with different concentrations of theantagonists. Vertical bars are ±S.E.M.

○ Control 1

Diltiazem 10⁻⁷ M (N=4)

Δ Control 2

Diltiazem 3.16×10⁻⁷ M (N=4)

 Control 3

Diltiazem 10⁻⁶ M (N=4)

FIG. 3 Effect of Test Compound 1 on Ca⁺⁺ -induced contractions of K⁺-depolarized guinea pig ileum.

Cumulative concentration response curves to Ca⁺⁺ were obtained prior to,and after, pre-incubation with different concentrations of Test Compound1.

○ Control 1

Test Compound 1 10⁻⁷ M (N=6)

Δ Control 2

Test Compound 1 3.16×10⁻⁷ M (N=6)

□ Control 3

Test Compound 1 10⁻⁶ M (N=6)

FIG. 4 Effect of Test Compound 2 on Ca⁺⁺ -induced contractions of K⁺-depolarized guinea pig ileum.

Cumulative concentration response curves to Ca⁺⁺ were obtained prior to,and after, pre-incubation with different concentrations of Test Compound2.

○ Control 1

Test Compound 2 10⁻⁶ M (N=9)

Δ Control 2

Test Compound 2 3.16×⁻⁶ M (N=7)

FIG. 5 Effect of Test Compound 3 on Ca⁺⁺ -induced contractions of K⁺-depolarized guinea pig ileum.

Cumulative concentration response curves to Ca⁺⁺ were obtained prior to,and after, pre-incubation with different concentrations of Test Compound3.

○ Control 1

Test Compound 3 10⁻⁶ M (N=5)

Δ Control 2

φ Test Compound 3 3.16×10⁻⁶ M (N=7)

□ Control 3

Test Compound 3 10⁻⁵ M (N=5)

FIG. 6 Schild plot of the antagonistic effects of d-cis-diltiazem andlactamimides.

Plots of log (dose ration -1) against -log [M]gave straight lines whichyielded mean pA₂ values (95% confidence interval) and mean slopes(±S.D.) as follows: d-cis-diltiazem 7.38 (7.18-7.84), 1.00 (0.15); TestCompound 1 7.27 (6.95-8.12), 0.94 (0.21); Test Compound 2 6.59(6.33-7.17), 1.02 (0.20); Test Compound 3 6.66 (6.31-7.44), 0.89 (0.16).Data were obtained from calcium dose-response curves obtained to 40 mMK⁺ -depolarized guinea pig ileum preparations.

○ Diltiazem

Test Compound 1

Δ Test Compound 2

Test Compound 3

FIG. 7 Correlation between displacement of [³ H]d-cis-diltiazem andantagonism of Ca⁺⁺ -induced contractions.

The negative logarithm of the inhibitory constant (pKi, M) against [³H]d-cis-diltiazem binding in rat brain membranes was derived from theIC₅₀ by the Cheng and Prusoff (1973) method and is plotted against thepA2 value (M) obtained by the method of Arunlakshana and Schild (1959)using antagonism of Ca⁺⁺ -induced contraction of the K⁺ -depolarizedguinea pig taenia or ileum preparations. The correlation co-efficient(r=0.87, p<0.001) and the slope (0.90) were calculated by linearregression analysis.

We claim:
 1. A method of effecting calcium antagonism in a patient inneed thereof which comprises administering to the patient a calciumantagonism effective amount of a compound of the formula ##STR44##wherein Z is hydrogen or lower alkyl of from 1 to 4 carbon atoms;n is aninteger of from 3 to 16; and R is 1- or 2- adamantyl or 1- or 2-norbornyl
 2. The method of claim 1 wherein n is the integer
 11. 3. Themethod of claim 1 wherein R is 2-norbornyl.
 4. The method of claim 3wherein n is the integer
 11. 5. The method of claim 1 wherein thecompound is 2-(2-norbornylimino)azacyclotridecane or a pharmaceuticallyacceptable salt thereof.